This application is in response to the CREG DCT-4, announcement of 1/12/78 Research Teams for Antitumor Drug Development. We propose to continue an innovative and productive drug development program at the USC Cancer Center carried out in a multidisciplinary fashion by experienced investigators. The funding requested is primarily for drug synthesis, but our team has the capability, in addition, to screen compounds we synthesize against cultured leukemic cells and a variety of rodent tumors, to carry out biochemical and enzymatic studies of their mechanism of action, and to determine their pharmacology and pharmacokinetics in animals. We are recruiting a preclinical toxicologist, and have experienced clinicians who are eager to do Phase I and II clinical trials of drugs that we develop. We propose 7 projects: 1) Synthesis and development of potential chemoimmunotherapeutic agents (Uricytin and Mimosine Derivatives). Uricytin is highly active against slow growing solid tumors and has an unusual mode of action; 2) Synthesis of novel compounds designed to bind specifically to DNA. Simplified structures should hydrogen-bond to GC pairs across th DNA double helix; 3) Synthesis and biological evaluation of 3-deazaguanine derivatives. Deoxyribonucleosides should improve the activity of a compound that is strikingly effective against slow growing solid tumors; 4) Synthesis of new inhibitors of thymidylate synthetase. This is a key chemotherapeutic target enzyme; 5) Synthesis of 2- and 8-phosphorus substituted purine isosteres. These are new heterocycles; 6) Synthesis of acteylenic "suicide" inhibitors of chemotherapeutic target enzymes -dihydroorotate dehydrogenase, ribonucleotide reductase, dihydrofolate reductase, cytidine deaminase; 7) Synthesis of transition-state analog inhibitors of chemotherapeutic target enzymes - glutamine synthetase and polyglutamate synthetase. Many of these compounds are phosphonates.